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Discovery: Important additional function protective eye protein Rare eye diseases: A glance at Stargardt disease
CLINICAL | OPHTHALMOLOGY Discovery Important additional function of protective eye protein
The lens of the human eye comprises a highly concentrated protein solution, which lends the lens its great refractive power.
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ROTECTIVE PROTEINS PREVENT
these proteins from clumping together throughout a lifetime. A team of scientists from the Technical University of Munich (TUM) has now uncovered the precise structure of the alpha-A-crystallin protein and, in the process, discovered an
P
important additional function.
The refractive power of the human eye lens stems from a highly concentrated protein solution. These proteins are created during embryonic development and must then function for a whole life, as the lens has no machinery to synthesise or degrade proteins.
When lens proteins are damaged, the result is cataract – a clouding of the lens – or presbyopia. This is where protective proteins come in. They ensure that the proteins of the eye retain their form even under adverse environmental influences.
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STRUCTURE OF A MULTIFACETED PROTEIN
Attempts to determine the structure of alpha-A-crystallin were unsuccessful for over 40 years. The breakthrough came for a research team led by the TUM professors Sevil Weinkauf, professor of electron microscopy and Johannes Buchner, professor of biotechnology, by combining cryo-electron microscopy, mass spectrometry, NMR spectroscopy and molecular modelling. "Alpha-A-crystallin is extremely multifaceted," says Sevil Weinkauf. “This makes it very difficult to determine its structure. It was only after developing a new strategy for data analysis that we were able to demonstrate that in solution it takes on different structures with 12, 16 or 20 subunits”.
PROTECTION AGAINST OXIDATION
The typical function of protective proteins is to help other proteins maintain their form when stressed, by high temperatures, for example. This is why they are also referred to as chaperones.
Alpha-A- and alpha-B-crystallin, too, have this function. In addition, human alphaA-crystallin has two cysteine residues. The sulphur atoms in these residues can form disulphide bridges. In-depth biochemical studies have shown that this bridging has a significant impact on various properties of the protein molecule. "A common theory is that the disulphide bridges result from damage to the protein, for example through oxygen," says Johannes Buchner. "Our results suggest that alphaA-crystallin might play an active role in protecting other proteins from oxidation."
MOTIVATION FOR FURTHER RESEARCH
Oxidised alpha-A-crystallin can even transfer the existing disulphide bridge to other proteins. "This ability corresponds to that of a protein disulphide oxidase," says Christoph Kaiser. “Alpha-A-crystallin can influence the redox state of other lens proteins. This function also explains why roughly half of the alpha-A-crystallin’s in embryos already have such disulphide bridges.”
“Around 35% of all cases of blindness can be attributed to cataracts, says Sevil Weinkauf. “The molecular understanding of the functions of eye lens proteins forms an essential basis for developing prevention and therapy strategies. The realisation that alpha-A-crystallin also plays an important role in protecting against oxidation will now spawn further research."
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